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Preparation method of azilsartan intermediate

A technology of ethoxy and hydroxyaminomethimino, which is applied in the field of preparation of azilsartan intermediates, can solve the problems of impossibility and low yield, and achieve the goal of improving efficiency, increasing yield and reducing amide impurities Effect

Inactive Publication Date: 2012-02-08
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the yield in the literature can reach 90%, it is obviously impossible to achieve it in practice, and the yield is very low

Method used

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  • Preparation method of azilsartan intermediate
  • Preparation method of azilsartan intermediate

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Experimental program
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Effect test

Embodiment 1

[0018] 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylic acid methyl ester (0.4g, 0.97mmol), 50% aqueous solution of hydroxylamine (0.33g , 4.9mmol), triethylamine (0.1g, 0.97mmol) in ethanol (10ml) was refluxed for 48h, cooled and crystallized, filtered to obtain the title compound 0.2g, yield 46.3%. After 48 hours of reaction, the liquid phase data of the reaction liquid showed that amide impurity: product (area ratio of liquid phase spectrum): raw material = 37.37: 54.52: 0.42.

Embodiment 2

[0020] 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylic acid methyl ester (2g, 4.9mmol), 50% aqueous hydroxylamine solution (3.43g, 49mmol), triethylamine (0.5g, 4.9mmol) in ethanol (20ml) was refluxed for 24h, cooled and crystallized, and filtered to obtain 1.52g of the title compound with a yield of 70.4%. After 24 hours of reaction, the liquid phase data of the reaction liquid showed that amide impurity: product (area ratio of liquid phase spectrum): raw material = 5.04:79.66:0.

Embodiment 3

[0022] 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylic acid methyl ester (0.4g, 0.97mmol), 50% aqueous solution of hydroxylamine (1.0g , 14.5mmol), triethylamine (0.1g, 0.97mmol) in ethanol (10ml) was refluxed for 20h, cooled and crystallized, and filtered to obtain 0.31g of the title compound with a yield of 71.7%. After 20 h of reaction, the liquid phase data of the reaction liquid showed that amide impurity: product (area ratio of liquid phase spectrum): raw material = 7.17:78.2:0.

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Abstract

The invention relates to the technical field of azilsartan intermediate preparation method. According to the invention, a compound 1-[(2'-cyanobiphenyl-4-group)methyl]-2-ethoxy benzimidazole-7-methyl carboxylate is subject to a reaction with an aqueous solution of hydroxylamine, such that the intermediate is prepared. In prior arts, amide impurities with an amount equal to that of the products are generated. With the method provided by the invention, the impurities are greatly reduced, such that the yield is increased. In prior arts, the reaction time is 48 hours, and yet a small amount of raw materials is not reacted. With the method provided by the invention, the reaction time is 24 hours, and the reaction is sufficiently carried out, such that the efficiency is improved. In a post-processing process, complicated steps of acid extraction and alkali ionization are not required. When the reaction id finished, the materials are cooled, and the target product can be precipitated directly.

Description

technical field [0001] The present invention relates to the intermediate 2-ethoxyl-1-[(((2'-hydroxyaminomethylimino)biphenyl)-4-yl)methyl]-1H-benzimidazole- The preparation method of methyl 7-carboxylate technical field. Background technique [0002] Azilsartan is a selective angiotensin II receptor antagonist with antihypertensive and central nervous effects. The preparation and therapeutic use of azilsartan have been described in the specification of Chinese patent CN92105152. The synthesis of azilsartan is described in the above patent specification, wherein the compound of formula (I), 2-ethoxyl-1-[(((2'-hydroxyaminomethylimino)biphenyl)-4 -yl)methyl]-1H-benzimidazole-7-carboxylic acid methyl ester is an important intermediate in the synthesis of azilsartan. [0003] [0004] The method for preparing the compound of formula (I) has been described in the publication J.Med.Chem, 1996, Vo39(26), 5528-5235, and also described in the specification of Chinese patent CN92...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
Inventor 岑均达束蓓艳吴雪松
Owner SHANGHAI INST OF PHARMA IND
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